Following up on last week's post on pearl mussel longevity and antioxidants (or not), here's more on the relationship between longevity and environmental temperature in cold-blooded species:

Munch and Salinas looked at lifespan data from laboratory and field observations for over 90 species from terrestrial, freshwater, and marine environments. They studied organisms with different average longevities - from the copepod Arcartia tonsa, which has an average lifespan of 11.6 days, to the pearl mussel Margaritifera margaritifera, which has an average lifespan of 74 years. They found that across this wide range of species, temperature was consistently exponentially related to lifespan.

The relationship between temperature and lifespan that Munch and Salinas found through data analysis was strikingly similar to the relationship that the metabolic theory of ecology (MTE) predicts. The MTE is a modeling framework that has been used to explain the way in which life history, population dynamics, geographic patterns, and other ecological processes scale with an animal's body size and temperature.

"You can think of an animal as a beaker in which chemical reactions are taking place," said Salinas. "The same rules that apply to a liquid inside a beaker should apply to animals. Chemists have a relationship for how an increase in temperature will speed up reaction rates, so the MTE borrows that relationship and applies it - with some obvious caveats - to living things."

Scientists in the audience can find the paper at PNAS. The lesson proposed here, I think, is that the study of comparative longevity between species - largely undertaken to gain insight into aging in higher species, and partly in search of mechanisms that might one day be introduced into a re-engineered human metabolism - might benefit from skipping over cold-blooded animals. If the overwhelming majority of differences can be explained by temperature, then the odds of finding something interesting and new are far lower than for investigations of warm-blooded species.

Which is not to say that I think searching for ways to alter human biochemistry is a good way ahead. It'll happen, because a large research community is presently heading in that direction, but I don't see it being either (a) rapid, or (b) very helpful for those of us who will be old when results start to emerge. Slowing aging down doesn't do much for those who are already old.

Munch, S., & Salinas, S. (2009). Latitudinal variation in lifespan within species is explained by the metabolic theory of ecology Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0900300106

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I'm sure you all know by now that restricting the amino acid methionine in the diet provides many of the health and longevity benefits of calorie restriction - in mice, at least. This is only the case for methionine, not any of the other essential amino acids that must be obtained through diet, and the resulting changes in biochemistry are not exactly the same as calorie restriction. This suggests that, for example, the loss of visceral fat associated with calorie restriction also plays an important role in extended healthspan and longevity.

Per recent research, it looks like too much methionine is a bad thing - biochemical measures of damage and good operation that are improved by lowering methionine intake are instead made worse when methionine is supplemented in the diet. This worsened set of metabolic processes occurs in addition to any further unpleasant effects produced by the visceral fat tissue most of us would gain in boosting our methionine intake the easy way - by eating more.

Methionine restriction without energy restriction increases, like caloric restriction, maximum longevity in rodents. Previous studies have shown that methionine restriction strongly decreases mitochondrial reactive oxygen species (ROS) production and oxidative damage to mitochondrial DNA, lowers membrane unsaturation, and decreases five different markers of protein oxidation in rat heart and liver mitochondria. It is unknown whether methionine supplementation in the diet can induce opposite changes, which is also interesting because excessive dietary methionine is [damaging to the liver] and induces cardiovascular alterations.

Because the detailed mechanisms of methionine-related [liver demaage] and cardiovascular toxicity are poorly understood and today many Western human populations consume levels of dietary protein (and thus, methionine) 2-3.3 fold higher than the average adult requirement, in the present experiment we analyze the effect of a methionine supplemented diet on mitochondrial ROS production and oxidative damage in the rat liver and heart mitochondria.

...

It was found that methionine supplementation increased mitochondrial ROS generation and percent free radical leak in rat liver mitochondria but not in rat heart. In agreement with these data oxidative damage to mitochondrial DNA increased only in rat liver, but no changes were observed in five different markers of protein oxidation in both organs. ... These results show that methionine supplementation in the diet specifically increases mitochondrial ROS production and mitochondrial DNA oxidative damage in rat liver mitochondria offering a plausible mechanism for its [ability to cause liver damage].

Less oxidative damage should be taken as better, although it's not always that simple; in some circumstances a little oxidative damage can spur the body to better repair and prevention efforts in the future. Here, however, more oxidative damage is a bad thing. You'll recall the role of mitochondrial reactive oxygen species (ROS) in the damage of aging per the mitochondrial free radical theory of aging - increased damage to mitochondria and increased production of mitochondrial ROS are not good for long term health.

The lesson to take away from this - as for many other related research results - is that diet affects your long term prospects for health and degenerative aging on a sliding scale that is measured in calories and methionine intake. More calories and more methionine is worse for you. Fewer calories and less methionine, assuming you're still obtaining the optimum level of required nutrients, is better for you.

Gomez, J., Caro, P., Sanchez, I., Naudi, A., Jove, M., Portero-Otin, M., Lopez-Torres, M., Pamplona, R., & Barja, G. (2009). Effect of methionine dietary supplementation on mitochondrial oxygen radical generation and oxidative DNA damage in rat liver and heart Journal of Bioenergetics and Biomembranes DOI: 10.1007/s10863-009-9229-3

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We'll start off today's post with a quick refresher on the present state of knowledge regarding antioxidants and life span in laboratory animals. Antioxidants are compounds that neutralize oxidants, such as the reactive oxygen species produced by your mitochondria that are implicated in the damage of aging. In theory, neutralizing those damaging oxidants before they can cause harm to your cellular machinery will lead to a lesser accumulation of cellular and tissue damage over time, and thus a slower rate of aging. Aging, after all, is no more than the accumulation of damage and the body's response to that damage.

Oxidant compounds also play important roles in the body's signaling mechanisms, however, so it's far from the case that we can declare all oxidants bad. What do researchers presently know?

• Many studies show that ingested antioxidants do nothing positive, and might actually be bad for longevity by interfering in beneficial mechanisms like exercise.

• The body produces a range of different natural antioxidants. Long-lived species seem to maintain the same levels of these compounds throughout life, but there's no correlation between levels of natural antioxidants and life span differences between similar species.

• Manipulating levels of natural antioxidants through gene engineering has produced all sorts of contradictory results, shifting life span in a variety of species in either direction. In some cases completely deleting the genes associated with generating these antioxidants extends life - not what you'd expect.

• However, antioxidant compounds can be engineered to be targeted to the mitochondria in your cells. This is demonstrated to extend life span in mice, using either antioxidants produced by the body or ingested artificial compounds.

At which point most people will throw up their hands and wait for the scientists to figure out what's going on here. You can't ignore the mice that are living 15-30% longer due to the targeted antioxidants, but equally you can't ignore the weight of other research in which boosting antioxidants doesn't increase life span. Personally, I still think it's down to the targeting, at least until some new work arrives to prove that thesis false.

In any case, the paper I wanted to point out today is another example of boosting natural antioxidants in a mammal and obtaining no benefit to life span.

Genetic manipulations of Mn superoxide dismutase (MnSOD), SOD2 expression have demonstrated that altering the level of MnSOD activity is critical for cellular function and life span in invertebrates. In mammals, Sod2 homozygous knockout mice die shortly after birth, and alterations of MnSOD levels are correlated with changes in oxidative damage and in the generation of mitochondrial reactive oxygen species.

In this study, we directly tested the effects of overexpressing MnSOD in young (4-6 months) and old (26-28 months) mice on mitochondrial function, levels of oxidative damage or stress, life span, and end-of-life pathology. Our data show that an approximately twofold overexpression of MnSOD throughout life in mice resulted in decreased lipid peroxidation, increased resistance against paraquat-induced oxidative stress, and decreased age-related decline in mitochondrial ATP production. However, this change in MnSOD expression did not alter either life span or age-related pathology.

Which muddies the water still further, given that we'd - perhaps naively - expect the biochemical changes listed above to be accompanied by at least some associated benefit to life span.

Jang, Y., Perez, V., Song, W., Lustgarten, M., Salmon, A., Mele, J., Qi, W., Liu, Y., Liang, H., Chaudhuri, A., Ikeno, Y., Epstein, C., Van Remmen, H., & Richardson, A. (2009). Overexpression of Mn Superoxide Dismutase Does Not Increase Life Span in Mice The Journals of Gerontology Series A: Biological Sciences and Medical Sciences DOI: 10.1093/gerona/glp100

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It is only in the last couple of years that clinical trials have started for autologous stem cell therapies in the US. Or, to put it another way, for some time now unelected and largely unaccountable employees of the US government have forbidden US residents - on pain of criminal prosecution - from offering or making their own decisions about a medical technology commercially available elsewhere in the world. All the while, these bureaucrats impose vast costs on medical development concerns by insisting on largely pointless trials, continuing far past any reasonable trade-off between risk and reward, thereby greatly postponing the commercial introduction of these technologies in the US.

Do you have responsibility for, or even the ability to make your own medical choices? Not according to people in positions of power at the FDA. Regulation in medicine has largely become an exercise undertaken for its own sake, as is the end result of any centralization of power. No-one's interests are being served save for those of the career bureaucrats in charge of forbidding new things. Everyone else gets to suffer due to the ball and chain shackled to medical progress, and due to being forbidden the basic, fundamental freedom to choose how to treat their own medical conditions.

But back to the science, what little of it is presently permitted to proceed.

An autologous therapy is one in which stem cells are taken from the patient, multiplied many times over in cell cultures, and then returned en mass to spur regeneration that the body would normally not accomplish on its own. Here, Scientific American updates us on an ongoing trial:

The first person to receive a new cardiac stem cell treatment in a U.S. Food and Drug Administration clinical trial is doing well, it was announced last week. ... Jones, whose heart tissue is permanently scarred and weakened by two previous heart attacks, suffers from congestive heart failure

...

The new approach, using a patient's adult stem cells to regenerate healthy heart tissue, is currently in phase I clinical trials to test for safety. The procedure consists of removing healthy heart tissue from the patient, purifying the stem cells from the material, and allowing the stem cell population to grow. Once ready, the stem cells are reintroduced into the scarred region of the heart using a minimally invasive technique.

Since the re-injection of his own stem cells on July 17, Jones' heart has increased its ability to pump blood by about 5 percent. Jones commented in the University of Louisville School of Medicine press release that he felt so good he might "even start jogging again."

The doctors will continue monitoring Jones every few months for the next two years to measure his recovery. There are currently 13 more patients going through the phase I trial, and the researchers hope to eventually test a total of 20 patients.

Now ask yourself, why can't anyone with heart disease and the necessary funds just up and do the research on the treatment and choose to try this within the borders of the US? Because a faceless bureaucrat has decided that it is forbidden, and that anyone who offers this treatment must be jailed. Welcome to the land of the free.

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Looking back from the perspective of 2035, I guess we should all be surprised that it took so long. The Vegas Group came together formally sometime in 2016, though the first kick-off meeting was the year prior at one of the bi-annual conventions for longevity research held in California. By that time, more than a dozen gene manipulations and other biotechnologies had been shown to significantly extend life in mice, but no progress was being made to develop these technologies for human use. The Vegas Group was a natural outgrowth of a decade of advocacy and anticipation for human enhancement technologies, coupled with the frustrating realization that no such technologies would be meaningfully developed, never mind made available to the public, under the regulatory regimes then in place in the US and Europe.

There were initial fractures in the Vegas Group around the course of political change versus direct action - which led to the formation of another influential movement discussed elsewhere - but by 2017 the direct action contingent of the Vegas Group consisted of about a hundred people all told. Their declared objective was a distributed collaborative effort to (a) develop human versions of the most successful longevity and metabolic enhancements demonstrated in mice, and (b) cultivate hospitable medical groups in the Asia-Pacific countries. When these technologies were developed, the founding members would cast lots and carefully test upon themselves, in rotation, and though the agency of medical centers in Asia. In doing this the hope was to spur change in the public view and greater progress in the commercialization of these technologies - and of course to gain access to manipulations that were greatly extending life in mice. "Pulling the big red lever," as one of the founders said, a venture where altruism and greed collide to best effect.

By this time, biotechnologies had become cheap enough to enable a growing amateur development community, akin to the hackers of the 1970s and open source movement of the 1990s and onward, and it is this community, stirred up and cultivated by the core Vegas Group, that ensured success. It was a challenge, a middle finger to US authorities who were at that time attempting to shut down the open biotech movements, and a tangible way to prove that the "priesthood of the universities is done and gone." Of course, members of that priesthood pitched in to help, some to the detriment of their careers, others clandestinely.

By 2019, the first round of therapies took place amongst the founding Vegas Group members. This happened to some local fanfare in Singapore, milked for effect by the sponsoring parties. About half of the modifications to genes and repair procedures for the damage of aging were successful, as shown by assays and testing, but no serious side-effects occurred - a lot of prestige in the broader amateur biotech community rested on getting that part right at least. So there, in 2019, you have some of the first humans walking around with replaced mitochondria, cleaned-out cells, manipulated myostatin genes, addition of bacterial genes to eliminate obesity, and so forth. Strangely, it met with less interest in the mainstream press than you might expect - the pop-sci and scientific press release services wouldn't touch it.

Really, that's when the accident should have happened, but with the benefit of hindsight I think that people became complacent. The seventeen deaths in 2021 were avoidable - some of the Vegas Group were emboldened by earlier successes and rushed a new discovery, underestimating the risk. By that time more than fifty people - a core of the original Vegas Group, new members, and new offshoots of the group elsewhere in the world - had been successfully modified in ways demonstrated to extend life or improve the functioning of biochemistry in mice, and were leading normal lives. A few of the older group members had died, but not of any cause linked to their experimental treatments. The methods for making these modifications to humans were freely available online, and within the reach of perhaps a few hundred skilled amateur biotechnologists. They had promptly been outlawed by most European and the US regulatory authorities.

The commercial outgrowth of the Vegas Group was by this time also underway. Two companies affiliated with the original founding members and two more working independently on the science were striding towards commercial offerings of the technologies. None were based in the US, of course, and all but one were structured to take advantage of the trends in medical tourism from America and Europe. Even at ruinous early-adopter rates, as a luxury good for the wealthy, two of these companies went on to make their founders fabulously wealthy in a very short time.

Sadly, it was to be another decade before we came to where we are today - the first signs that US regulators might finally cease their prohibition of longevity-inducing and other enhancement technologies now offered widely in Asia and safely used by ever-increasing numbers of people.

From the perspective of the mainstream US scientific community, we still don't know if these alterations work as advertised on human longevity. The case is pretty much open and closed on calorie restriction in humans and other primates now, finally, after decades of debate and new data, but it may be 2055 before researchers are willing to move beyond measurement of markers and biochemical changes to acknowledge actual benefits to life expectancy to the procedures pioneered by the Vegas Group. Meanwhile, people are improving themselves.

Strangely, the Vegas Group has faded from view, a historical curiosity of the online cyclopedias that is now supplanted in the "official" histories by the companies that rose up from their efforts. As a sign of success, being forgotten in the wake of the vessel you help to launch has something going for it - burying the daredevils is the first action of a successful industry setting up for the long term.

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The freshwater pearl mussel (Margaritifera margaritifera) is a very long-lived beast, though as for many of these species its life span is poorly studied. There are too many bivalves and not enough researchers - remember that we live in a world in which we can't even determine lobster ages with any degree of certainty. Like many bivalves, lobster biochemistry doesn't seem to change with age in any usefully measurable way.

You might recall research into the longevity of another bivalve, the arctic quahog clam, that suggests its longevity is a matter of excellent natural antioxidants:

The ocean quahog Arctica islandica is the longest-lived of all bivalve and molluscan species on earth. Animals close to 400 years are common and reported maximum live span around Iceland is close to 400 years. High and stable antioxidant capacities are a possible strategy to slow senescence and extend lifespan

Compare that with this recent open access paper on the pearl mussel wherein the researchers found a different story when looking at superoxide dismutase (SOD) and catalase (CAT):

Free radicals are extremely reactive and produce damage and modify cell functions. Furthermore, superoxide dismutase and catalase are believed to play a key role in the enzymatic defence of the cells. Indeed, some authors have argued that reduced free-radical damage could explain increased longevity. Margaritifera margaritifera is one of the longest-lived animals in the world (up to 100-200 years). Furthermore, this organism may serve as a useful model for gerontologists interested in exploring the mechanisms that promote long life and the slowing of senescence. The present study estimated for the first time individual enzymatic activity for superoxide dismutase [and] catalase in tissue preparations of gills, digestive glands and mantles of two natural populations of M. margaritifera.

...

the SOD levels in the digestive gland of the short-lived marine bivalve Mytilus edulis are of a similar order to those shown by the long-lived M. margaritifera, and the CAT levels were lower in M. margaritifera. Although the activity of these enzymes in M. margaritifera slightly increases with age, we cannot find a correlation between CAT and SOD activity in respect to age.

So the mussels don't have high levels of antioxidant enzymes, but they are stable with age. Different populations have quite radically different levels of SOD and CAT, uncorrelated to longevity, and which the authors attribute to local environmental conditions and growth rates:

Bauer (1992) analysed the variation in longevity across Europe in M. margaritifera, and he found that as temperature decreases (toward the North), the metabolic rate declines and the rate of growth decreases and this leads to a long life. According to Bauer (1992) latitude (and therefore metabolic rate) alone explained around 50% of the variation in maximum life-span (the remaining variation attributed in part to differences in hydrochemistry). Spanish populations (including those of the rivers Eo and Masma) of freshwater pearl mussel show the highest growth rates from Europe and their variation in maximum life-span is comparable to that reported for others living farther North; growth rates also showed remarkable differences (San Miguel et al., 2004) even within the same river (for example, the Eo River). Indeed, the huge variation in SOD and CAT levels found in the present study can be principally interpreted as an adaptation to the unpredictable and changing nature of freshwater natural habitats.

Once again, one is left pondering the role of naturally produced antioxidant compounds. Clearly demonstrated to be related to longevity in some studies, and much more ambiguous in others. Here, ambiguous. All this tells us is that consistent levels of natural antioxidants with age are a good marker for species that are extremely long-lived, which says nothing about whether this is a contributory cause or an effect of other mechanisms that ensure longevity. Further, here we have another example of a long-lived species with similar or less active antioxidant enzymes than a much shorter-lived cousin.

No-one ever said the biology of aging was simple.

CARLOS FERNÁNDEZ, EDUARDO SAN MIGUEL, & ALMUDENA FERNÁNDEZ-BRIERA (2009). Superoxide dismutase and catalase: tissue activities and relation with age in the long-lived species Margaritifera margaritifera Biological Research, 42 (1), 56-57 DOI: 19621133

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Why should those of us interested in engineered longevity pay attention to research and drug development for a type of amyloidosis called TTR amyloid polyneuropathy (ATTR-PN) or Familial Amyloid Polyneuropathy (FAP), a condition that likely has only around 10,000 sufferers worldwide? The answer is that forms of TTR amyloidosis have a much broader relevance to degeneration and death in the oldest old, those centenarians who have survived or avoided all other forms of age-related disease. The "TTR" in the condition name refers to transthyretin, a protein that becomes misfolded and forms deposits outside cells that then cause all sorts of issues:

Coles argues [that supercentenarians] aren't perishing from the typical scourges of old age, such as cancer, heart disease, stroke, and Alzheimer's Disease. What kills most of them, he says, is a condition, extremely rare among younger people, called senile cardiac TTR Amyloidosis. TTR is a protein that cradles the thyroid hormone thyroxine and whisks it around the body. In TTR Amyloidosis, the protein amasses in and clogs blood vessels, forcing the heart to work harder and eventually fail. "The same thing that happens in the pipes of an old house happens in your blood vessels," says Coles.

Earlier this year, I pointed out one research group working on a way to treat this class of conditions:

Prof Pepys was working then in collaboration with Roche. But the Swiss pharmaceutical giant eventually pulled out. "While we had promising early results [with CPHPC] they were not enough to benefit patients with advanced disease," he says. "Something more dramatic is needed."

That something turns out to a combination of CPHPC with an antibody - a molecular guidance system designed to seek out amyloid deposits in vital organs. Now Prof Pepys has reached an agreement with another big pharmaceutical group, UK-based GlaxoSmithKline, to collaborate on producing a treatment for amyloidosis based on the CPHPC-antibody combination.

My attention was recently directed to FoldRx, a company currently trialing another drug aimed at interfering in the process by which TTR amyloids form. Their intent is treatment of Familial Amyloid Polyneuropathy:

The drug [tafamidis] stabilizes wild-type and variant TTR, prevents misfolding of the protein by preventing tetramer dissociation and inhibits the formation of TTR amyloid fibrils. ... No disease progression was observed in 60% of tafamidis patients as compared to 38% of placebo patients after 18 months treatment. In addition, there was a significant deterioration in [quality of life] in placebo patients compared to those treated with tafamidis after 18 months.

Small steps forward. Clinical trials and multiple groups working on the underlying science are a good sign for future progress in clearing up varying forms of amyloidosis, even if present results offer only incremental improvement.

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You'll recall that stem cells transplanted into the heart spur regeneration of damage, such as that caused by a stroke, through releasing growth factors and other signaling chemicals. Researchers have now demonstrated that a similar process can be made to happen in the brain:

Mice genetically engineered to have Alzheimer's performed markedly better on memory tests a month after mouse neural stem cells were injected into their brains. The stem cells secreted a protein that created more neural connections, improving cognitive function.

...

the stem cells were found to have secreted a protein called brain-derived neurotrophic factor, or BDNF. This caused existing tissue to sprout new neurites, strengthening and increasing the number of connections between neurons. When the team selectively reduced BDNF from the stem cells, the benefit was lost, providing strong evidence that BDNF is critical to the effect of stem cells on memory and neuronal function.

"If you look at Alzheimer's, it's not the plaques and tangles that correlate best with dementia; it's the loss of synapses - connections between neurons," Blurton-Jones said. "The neural stem cells were helping the brain form new synapses and nursing the injured neurons back to health."

This work is, obviously, performed in the context of trying to do something about Alzheimer's - if only by spurring the body to greater feats of ongoing repair rather than by altering the conditions that are causing damage - but I'm sure you can see the potential for more general application. Memory declines in everyone with age, and some fraction of that process is caused by damage to the same synaptic connections as are devastated by Alzheimer's. The memories are still encoded in there somewhere, but the brain has lost the connections needed to retrieve them, and in its default state of operation will not fix this situation.

If we can spur regeneration in a worn heart, then why not in a worn brain?

Those folk interested in human enhancement should also be pondering this research with some interest. What beneficial effects could be gained for memory and other aspects of the brain's performance in healthy people through accelerated growth of neural connections?

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The research community is rapidly reproducing the past ten years of stem cell technology demonstrations, using induced pluripotent stem (iPS) cells this time around. You'll recall that iPS cells are normal cells - usually skin cells - reprogrammed to act as though they are stem cells. The methodology is well within reach of any laboratory previously working on stem cells, and many research groups have dived into the fray since the first publication of the reprogramming method. Rapid progress has been made in a very short time, a characteristic state of affairs for biotechnology these days.

As a recent paper shows, iPS researchers have reached the point of demonstrating regeneration of damaged hearts in mice. Non-scientists might prefer the press release to the original paper:

The ultimate goal is to use iPS cells derived from patients to repair injury. Using a person's own cells in the process eliminates the risk of rejection and the need for anti-rejection drugs. One day this regenerative medicine strategy may alleviate the demand for organ transplantation limited by donor shortage, the researchers say.

...

The Mayo Clinic team genetically reprogrammed fibroblasts via a "stemness-related" human gene set to dedifferentiate into an iPS cell capable of then redifferentiating into new heart muscle. When transplanted into damaged mouse hearts, iPS cells engrafted after two weeks, and after four weeks significantly contributed to improved structure and function of the damaged heart.

At this rate, I'd guess at it being no more than another few years before the first clinical trials in humans are getting started. They will mirror the trials that have taken place for heart disease in recent years, using much the same methods, but replacing stem cells cultured from the patient's existing stem cell populations with stem cells created from scratch using a skin sample.

From a high level perspective, you might view this sort of early application of iPS cell technology as an infrastructure improvement for stem cell medicine - a similar end result, but accomplished more rapidly and with less cost. That will make it possible for more groups to offer these services, which allows a more competitive marketplace, which in turn spurs more learning and research.

Nelson, T., Martinez-Fernandez, A., Yamada, S., Perez-Terzic, C., Ikeda, Y., & Terzic, A. (2009). Repair of Acute Myocardial Infarction With Induced Pluripotent Stem Cells Induced by Human Stemness Factors Circulation DOI: 10.1161/CIRCULATIONAHA.109.865154

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I'll pull three short snippets from a recent RedOrbit article as illustrative of topics that crop up here every so often:

In the 1950s, the number of centenarians was estimated to be a few thousand worldwide. That figure is now estimated to be at more than 340,000, and rising.

...

According to Census Bureau estimates, Japan is expected to have the largest population of people over the age of 100 - 627,000 by 2050. The median age in Japan is expected to rise from 37 in 1990 to 55 by 2050.

...

The current life span is 78, but a recent poll conducted by the Pew Research Center found that an average of Americans would prefer to live to the age of 89, while one in five said they would like to live beyond age 90. Only 8 percent said they hope to live to see their 100th birthday and beyond.

If you have 8% of the population on your side, you can get a lot done. But fundamentally the issue is that most people live in the world of their parents and grandparents, their views on aging shaped by what has happened to people who did not have access to the technologies that will exist in 20 or 40 or 60 years time. When you're young, being old doesn't look all that great - and whatever self-protective rationalizations occur later in life, you were right. The experience and insight that comes with years of life is good, but degenerative aging is horrible, truly horrible.

People expect the course of life they have seen happen already to those they know best, not the course of life that is possible with biotechnology that will be developed over the next couple of decades. The trend in life expectancy is presently upward, a few months every year thanks new medical technologies that are but a tiny hint of what will come in years ahead. Extending those trends through a time of revolution in biotechnology is naive - pins stuck in the map because someone somewhere (such as the life insurance industry) needs an answer. If bloated regulatory powers win out and slow medical advances to a crawl, then yes, Japan will likely have only 600,000 centenarians in 2050. But for that to be the case, rather than a world in which people routinely undergo rejuvenation therapies and few die before reaching 100 years of age, we must collectively fail to achieve progress in biotechnologies aimed at repairing damaged human tissues.

For aging can be repaired, its damage removed through tools that can be visualized today, and the next 20 to 40 years are sufficient to see that goal accomplished. But that vast distributed development project will only take place if people want it to take place. If most people have little interest in living longer, because they assume degenerative aging is writ in stone and being older means being frail and suffering, then development will be slow and we'll all age to death.

Cheery thoughts. But recognizing the problem is an early step on the way to doing something about it.

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A recent Q&A session with biomedical gerontologist Aubrey de Grey, driving force behind the SENS Foundation can be found over at Next Big Future. A few excerpts:

Question: Tell us about the SENS foundation. What is its budget? How many research projects does it currently have underway?

Answer: SENS Foundation was created in April 2009 and took over the SENS research activities of the Methuselah Foundation (MF). We have a very limited budget at this point, initially consisting of the funds that had been donated to the MF for SENS research and had not already been spent. In essence we currently have a freeze on funding anything new right now. However, we are of course working extremely hard to change that!

...

Question: Is the mainstream scientific establishment becoming more receptive to your research and arguments?

Answer: Definitely. The derision that they previously met within most of the biogerontology community has become very much a minority view, as it's become more obvious that there is no scientific basis for dismissing SENS. The process has also been aided by the enthusiastic acceptance of the various SENS concepts by those whose work is most relevant to their development - researchers who are mostly not biogerontologists.

Question: What institutions currently fund your research? To what extent is your research constrained by insufficient funding?

Answer: Our research is not funded by any institutions (such as NIH), only by philanthropy. Its rate is massively constrained by insufficient funding: we could certainly spend 50 times what we currently have before we came close to running out of important projects to support.

You might link the budgetary constraints with de Grey's comments in the latest issue of Rejuvenation Research. When constraints on progress are primarily financial rather than technical, and when you have interested researchers and projects ready to go, then it's time to direct more effort towards persuading a broader audience that your goals are worthwhile and plausible.

Having watched this space of ideas fairly closely for a decade now, I can say that support for engineered longevity is far, far advanced from where it was when I was first trying to figure it all out. Yet in the bigger picture we're all still just getting started on the process of education, outreach, and the persuasion that leads to fundraising success.

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Following on from yesterday's post, I notice that Aubrey de Grey of the SENS Foundation will be speaking at the Singularity Summit in October of this year. The study of aging is, as he explains, a field on the cusp between the era in which all you can do is study and learn, and the era in which tools have advanced to the point at which you can apply that knowledge - here towards engineering greater human longevity. As with all times of transition, there are those members of the community who look forward in anticipation, and those who resist change:

Technologists, including those in medicine, are paid to turn knowledge into products. Scientists, by contrast, are paid to turn knowledge into more knowledge. Above all, this is because this hands-off, "curiosity-driven" approach to deciding what to study has proven remarkably successful, throughout the history of scientific endeavour, at giving rise to knowledge that technologists can duly take forward into means of improving humanity's quality of life. However, as funding for science has become ever more competitive, this happy state of affairs has begun to decay. Scientists are driven into ever greater specialisation, applying for funding only in the narrow area in which they are already acknowledged world leaders; this hinders the cross-fertilisation that is so essential for efficient progress.

Biogerontology, arguably alone among the biological sciences, has an additional problem: it is a field being transformed from a basic science into an applied, translational one as a result of advances made with other goals (mostly in regenerative medicine), and thus made predominantly by non-biogerontologists. Biogerontologists are thus faced with the particularly painful dilemma of either defending the field against the encroachment of these other specialities of which they are not the leading experts, or embracing the modernisation of their discipline at what may be at least short-term risk to their careers. Unfortunately, the former option is seductively easy, but it delays the advent of effective therapies against aging and thus potentially costs huge numbers of lives. I argue that biogerontologists have a duty to recognise, without further delay, that the fate of countless individuals rests on whether they make the courageous choice to embrace new approaches to aging with an open mind.

The broader summit looks to be an interesting event; there are certainly a wealth of leading lights from the transhumanist community listed on the program. Take a look and see what you think.

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The latest edition of Rejuvenation Research (volume 12, number 3) is available online - I'd already noted what I consider the most interesting scientific paper over at the Longevity Meme, an argument for DNA damage as an important cause of aging. Here, however, I'll note that this edition of the journal opens with a characteristically punchy editorial from biomedical gerontologist Aubrey de Grey:

A brief perusal of my publication record will reveal something about my recent activities that may - indeed, probably should - strike you as sad: I hardly contribute anything to the biogerontology literature any more, essentially restricting myself instead to my characteristic outbursts in this space and the occasional invited book chapter. Unltimately, however, this is not a reason for sympathy, because it is deliberate - a choice resulting from the changed relative importance to the crusade against aging of my two ways of contributing, to the science (the feasibility) and to the public debate (the desirability). In recent years, though resistance undoubtedly still festers within mainstream biogerontology, great progress has occurred in broadening the appreciation that applying regenerative interventions to aging may prove to be far more effective, far sooner, that the traditional approach of attempting to "clean up metabolism" and prevent its eventual pathogenic side effects from occurring in the first place.

Corresponding progress in enlightening people that defeating aging would be a good idea, however, has been quite considerably slower; hence my choice to devote an ever-greater proportion of my time - and of the pages of this journal - to that part of the equation.

I agree that progress on persuading interest in engineered longevity within the scientific community is moving more rapidly than it is in the broader population. Though it seems to me that most of the public-facing scientists continue to favor metabolic manipulation to slow aging rather than Strategies for Engineered Negligible Senescence-like research aimed at repairing damage, and also continue to believe that meaningful applications of this work lie beyond their remaining lifetimes.

Still, the course of longevity science will be a long haul ahead, and the goal at present is less getting things done and more building the self-sustaining, growing research community who will get things done. Today's technology demonstrations and applied research for SENS-like repair of damage are needed, of course, but beyond that the end goals of greatly extended healthy human lives and the elimination of degenerative aging require greater public support and understanding. Over periods of time measured in decades only those goals that are widely desired and appreciated have a good chance of being accomplished. It takes a lot of money and a great many people to move a field of medicine ahead - look at stem cell research as an example - and that doesn't tend happen out on the fringe of public interest.

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Let me direct your attention to the Campaign for Aging Research, a recently formed non-profit group that focuses on advocacy and research fundraising for engineered longevity. Their organizational viewpoint on the science is informed by the Strategies for Engineered Negligible Senescence (SENS), and the Campaign volunteers have a very post-blog, social network look to their online outreach efforts.

The Campaign for Aging Research is about "More time." More time to live, more time to understand the world and more time to discover. C.A.R offers a different perspective on life and the future. The same way we get contact lenses instead of accepting bad eye sight or take aspirin to overcome a strong migraine, aging is natural like the bad eye sight and the migraine, yet it is a handicap that can be overcome, and at the very least must be faced and dealt with like we would with a nasty virus or pandemic. Research always takes time - how much resources are invested affect the time that it takes to obtain results.

I don't know any of the folk involved, and I view this is a welcome sign. Progress in growing the advocacy community is measured, from any one personal perspective, by the number of people who come seemingly out of the blue to get things done. I'm all for more of that. The CAR message could use a little polish, but you can't fault the volunteers' earnest intent, which comes shining through. All in all, more fundraising for SENS research is a very good thing, and the more people working on it the better the long-term outlook.

A little digging - very little, Google makes everything easy - turns up this exchange on the Methuselah Foundation forums from a couple of months ago:

[Florin Capa] I have a few observations and some questions about The Campaign for Aging Research (C.A.R) ... Does anyone else know more about them

[Aubrey de Grey]: I do. Their founder, Charlie Warren, is based in the S Bay area and I have had extensive interaction with him. CAR does not at this point have any formal links with [SENS Foundation], but I can vouch for Charlie's commitment to allocate any funds he may attract in accordance with our recommendations. CAR obtained charitable (501c3) status just a few weeks ago.

So drop by their website, welcome CAR to the community if you haven't already, and offer them a helping hand if you like what they're doing.

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The latest set of podcasts from SAGE Crossroads examine the pharmaceutical industry point of view on aging research, which from a technical perspective basically boils down to building drugs to slow down aging by manipulating metabolism. For example, calorie restriction mimetics are presently hot, but are not the be-all and end-all of this field.

So I suppose I should start with this podcast, as it quickly illustrates some very important points to bear in mind when listening to anything on the topic of the pharmaceutical industry in the US.

#59 - Pharmaceuticals and Aging - The pharmaceutical industry's perspective on what will help the symptoms of aging

Dr. Michelle Dipp offers up an industry perspective on treating the symptoms of aging with drugs. She feels that the biggest challenges to the development of these medicines are scientific rather than rooted in policy, but she exudes confidence that we will tackle the problems of aging with pharmaceuticals in the near future.

Now bear in mind that (a) Dipp works for Sirtris, a company bought by GlaxoSmithKline, b) the FDA will not approve medicines to treat aging, as its bureaucrats do not classify aging as a condition to be treated, c) the FDA's regulatory reach has a hideous counterproductive effect on all progress in medicine, and d) the founders of Sirtris themselves have said this on the topic of regulation:

Why, despite the great range of potential applicable biotechnology, do we not see hundreds of millions of dollars invested in startups attempting to address the aging process? The answer is buried in this New York Times article on Sirtris: "Dr. Westphal and Mr. Sinclair stress that they are not working to 'cure' aging, a condition that, so far at least, is common to all humanity and that most physicians do not consider a disease. 'Curing aging is not an endpoint the federal drug agency would recognize,' Dr. Westphal says dryly. Instead, both men say, they are working to ameliorate the diseases of aging."

The big pharmaceutical companies are like any big company in a market dominated by government regulation rather than competition. In public they have to play the game in which you say that regulation is wonderful, and in private you use the system of regulation to make it very hard for new and disruptive competitors (meaning people who are striving to better serve customers and develop better products) to change your market in ways that inconvenience your profit margin. Progress is stifled. The rest of us have to suffer, sigh, and mentally shift all public representatives of companies in that market into the "politician, assume everything said is a self-serving lie" bucket.

Anyway, that said, the other two podcasts bear a look:

#57 - Pharmaceuticals and Aging - Can drugs be developed to treat the symptoms of aging?

LARRY MILLER: [When] I was heading aging at Glaxo Smith Kline, the issues that I faced were that I was very interested in developing medications for frailty and weakness in muscle for when people get old because when people get weak they usually stop eating and then they fall and break a hip and end up in the hospital and die potentially, but the regulatory apparatus isn’t there yet. Sarcopenia isn’t recognized as an official disease by the FDA, so the pathway to get drugs approved for frailty and to get more people mobile and into society is just not there

#58 - Pharmaceuticals and Aging - Overcoming the barriers of getting aging drugs to market

KYLE JENSEN: Now is getting the FDA to recognize these conditions, is this just a matter of lobbying them to expand their horizons or is there a better way to approach it?

WILLIAM EVANS: Exactly. I think there are a number of ways to approach it. One is to lobby. It is clear that public pressure helps to make the FDA think about some of these issues. I think that we are working with some of the professional societies like the Geriatric Society of America to also come to some agreement and consensus. Also what the FDA, I think, really likes to see with regard with potential new indications is not just consensus from the scientific community but also consensus from professional organizations, and I think that we are working towards that right now.

KYLE JENSEN: So do you see much hope in the next 5 years of getting some of these regulations changed?

I hope I'm not the only one who sees nothing but madness and waste in a system of development in which you have to spend years and countless dollars just to get permission to build better medical technology. The Soviet method of development - and look how well that worked! - is alive and well in the US medical regulatory establishment. It would be funny if we weren't all going to suffer greatly because of it.

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Over at the Speculist you'll find another anecdotal look at why it is we advocates for engineered longevity have lot of work yet to do. Building a large and dynamic research community akin to that formed to tackle cancer will require widespread support and acceptance of work to repair and reverse the damage of aging. A hundred thousand people die miserable age-induced deaths every day, and hundreds of millions more struggle with age-related degeneration and suffering - this horrifc toll dwarfs any other, natural or manmade. Yet, as I recently noted here, it seems that the first reaction of a great many people is to declare how terrible it would be to cure aging:

Those who think taking on aging is a "misuse" of medicine simply baffle me. If medical research came up with ways to eliminate cancer, heart disease, and diabetes, would anyone argue that those treatments represent a "misuse" of medicine? Why is it bad for people to die from those things but okay for them to die from something else?

Imagine somebody asks you to make a donation to the Juvenile Diabetes Research Foundation. Would you respond to that by saying, "Why? So those diabetes sufferers can continue their lives of self-serving hedonism?"

Or maybe someone asks you to support Race for the Cure, and you respond with: "Hey, wait a second. If all these women survive breast cancer, what's that going to do to Social Security?" Or how about: "Where will we get food and fresh water to support all these surviving women?" Or maybe: "I'm sorry, I can't help you. It just wouldn't be right to encourage these cancer sufferers to look at the natural progression of their lives as something malignant. Well, okay, granted - cancer is malignant, but you see what I'm saying."

No, you would never say anything like that, because only a moral cretin of truly world-class proportions would even think anything like that. But turn those cancer or diabetes victims into old people, and they become fair game - people whose continued existence is just too inconvenient to bear - people who need to die already, who it would be a misuse of medicine to help.

A certain self-destructive Malthusian current seems to flow through many of the more strident objections towards engineered longevity.

And yet, alongside the ethos of human rights and the development of heroic medicine, contemporary society appears estranged from its own humanity. To put it bluntly: it is difficult to celebrate human life in any meaningful way when people - or at least the growth of the number of people - are regarded as the source of the world’s problems. Alongside today’s respect for human life there is the increasingly popular idea that there is too much human life around, and that it is killing the planet. ... today’s Malthusians share all the old prejudices and in addition they harbour a powerful sense of loathing against the human species itself. Is it any surprise, then, that some of them actually celebrate non-existence? The obsession with natural limits distracts society from the far more creative search for solutions to hunger or poverty or lack of resources.

...

Life - and by extension, the necessary means and medical technology to make that life worth living - is the goal of healthy life extension. Oblivion and poverty are the goals of the modern Malthusian. This is a reminder once more that the greatest obstacle to healthy life extension research is not the technological hurdles, but rather those amongst us who would see us all age and die to satisfy their errant beliefs.

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Results from a long-running primate study of calorie restriction (CR) are becoming more definitive as the years pass. Two decades in, the reports continue to be consistent with the many, many other CR studies in animals and humans: eating fewer calories while still obtaining adequate nutrition slows down degenerative aging in primates.

Studying aging in monkeys takes patience. Mice and rats only live for a couple of years, while these monkeys can live to 40, and the average life span is 27 years. Now that the surviving monkeys have reached their mid- to late 20s, the Wisconsin group could glean how calorie restriction was affecting their life span. Sixty-three percent of the calorie-restricted animals are still alive compared to only 45% of their free-feeding counterparts. For age-related deaths caused by illnesses such as cardiovascular disease and cancer, the voracious eaters died at three times the rate of restricted monkeys: 14 versus five monkeys, respectively.

...

Researchers who study aging are split on how much stock to put in the study. Leonard Guarente, a molecular biologist at the Massachusetts Institute of Technology in Cambridge who has studied aging in yeast, believes that not enough monkeys have died yet to make definitive comparisons between the two groups. As of March, when Weindruch's group submitted the paper, about half of the colony was still alive. "The gap [in survival rates] may separate more, but it's still too early to tell," Guarente says. On the other hand, molecular biologist Matthew Kaeberlein of the University of Washington, Seattle, thinks the gap as it stands now is still compelling. He points to the difference in age-related deaths between the two groups as the more relevant statistic. "The fact that they see a significant effect at this point suggests there will be a robust effect when they finish the study," he says.

The original paper in Science won't add much more in the way of useful detail for most of you folk - the commentary in responsible news articles is probably more helpful. If you're familiar with the effects of calorie restriction in other mammals, this is basically a confirmation of what was the expected and most plausible outcome in rhesus monkeys. The practice of calorie restriction remains, as before, a good bet for healthy humans. A great weight of scientific evidence exists to back up that assertion, eating fewer calories won't cost you anything other than time spent learning the best practices, and this strategy is presently available to anyone who wants to try it.

Colman, R., Anderson, R., Johnson, S., Kastman, E., Kosmatka, K., Beasley, T., Allison, D., Cruzen, C., Simmons, H., Kemnitz, J., & Weindruch, R. (2009). Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys Science, 325 (5937), 201-204 DOI: 10.1126/science.1173635

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Rapamycin is a drug of interest because researchers know that the TOR gene (which stands for Target of Rapamycin, so you can probably guess the order of discovery) is involved the big tangled mess of biochemistry relating to the calorie restriction response. Less food while maintaining adequate nutrition modulates the functions of metabolism in ways that lead to longer lives and slower aging. Unless you've spent the past few years living in a basket, you'll know that this is of considerable interest to the gerontological and pharmaceutical research communities, and many efforts are underway to develop means of achieving or bettering this biochemical response without modifying diet.

Personally, I think this is all a sideshow of limited benefit in comparison to research that aims to repair and reverse the damage of aging rather than merely slowing it a little. But the sideshow has the main stage and the attention of the tent for now. Sideshow or not, it will produce a vast amount of new information on the way in which our biochemistry works - so it isn't a waste, it's just not very efficient if the end goal is for humans to live much longer in good health than they presently do.

But back to rapamycin. The news for today is that researchers ran lifespan studies on mice where rapamycin was administered comparatively late in life, yet still produced noteworthy gains in overall life expectancy. Via the Nature article:

Problems formulating the feed meant that the teams couldn't start the treatment until the mice were rather older than they had planned - 20 months of age, or the equivalent of about 60 years in human terms.

As it happened, this delay was a fortuitous accident. Compared with the non-drug-taking group, the lifespans of the mice given rapamycin increased by up to 14%, even though they were middle-aged when treatment began. Their life expectancy at 20 months shot up by 28% for the males and 38% for the females.

This is actually good enough to be worth running in the Rejuvenation Prize component of the MPrize for longevity science - it's about the same as the record for late onset calorie restriction started at that age. It has to be said that I'm surprised to see a presently available drug capture a similar level of additional longevity given the past few years of less stellar results from sirtuin-manipulating drugs.

Those of a more scientific mindset should take a look at the original paper. I'm wondering whether the diet of these mice was controlled for calorie restriction, so as to eliminate the old, old issue of drugs that make your mice eat less and thereby extend their lives that way. Given the researchers listed, I'd assume that care was taken here, but it's always worth checking.

Harrison, D., Strong, R., Sharp, Z., Nelson, J., Astle, C., Flurkey, K., Nadon, N., Wilkinson, J., Frenkel, K., Carter, C., Pahor, M., Javors, M., Fernandez, E., & Miller, R. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice Nature DOI: 10.1038/nature08221

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Unintentional poetry can sometimes be found amidst the drudgery of translating literature from one language to another. Spanish to English gifts us with "consumers of drugs of abuse," which serves as the point of attraction to here consider the relationship between aging and damaging ourselves, both proactively and through neglect. The full PDF is also freely available in both Spanish and English, lined up in parallel.

The aging or senescence process that follows maturation is characterized by time-related functional decline due to genetic, biochemical, physiological and anatomical degeneration in tissues and organ systems with time. Oxidative damage to mitochondrial DNA (mtDNA) in the heart and brain is inversely related to maximum life span of mammals, suggesting that accumulation of mtDNA damage is involved in the various disorders associated with aging, cancer and neurodegeneration. The suppression of stem/progenitor cell proliferation also contributes to the aging process, by reducing tissue regeneration and repair and ultimately reducing longevity. Another important factor is the intracellular deposition of lipofuscin granules (age pigment), a non-degradable polymeric material accumulated within lysosomes, which ultimately exacerbate oxidative stress levels in senescent cells.

Drugs of abuse can strongly contribute to these senescence accelerating factors in the brain. Methylenedioxymethamphetamine ('ecstasy') and methamphetamine were shown to promote deletions in brain mtDNA. Concerning stem/ progenitor cells, it has been shown that several opiates and psychostimulants, including ecstasy, decrease the self-renewal capacity of the hippocampus by diminishing the rate of proliferation of neural progenitors and/or by impairing the long-term survival of neural precursors. Chronic alcohol consumption induces lipofuscin deposition in neurons and heart cells. These facts provide interesting hints on the potential of these drugs in accelerating brain senescence.

Degenerative aging is no more than molecular and cellular damage and the (increasingly flailing) reactions of our biochemistry to adapt to, repair, or work around that damage. That we degenerate with age is a function of our present inability to repair the damage produced over a long life. This will change in years ahead with the inexorable advance of biotechnology, but even now we have a fair degree of control over some aspects of aging - over how fast we choose to damage ourselves. Exercise or lack of same looks likely to move life expectancy by a decade, for example.

A useful concept here is the division of aging into primary aging and secondary aging:

Primary aging is the gradual - and presently inevitable - process of bodily deterioration that takes place throughout life: the accumulation of biochemical damage that leads to slowed movements, fading vision, impaired hearing, reduced ability to adapt to stress, decreased resistance to infections, and so forth. Secondary aging processes result from disease and poor health practices (e.g. no exercise, smoking, excess fat and other forms of self-damage) and are often preventable, whether through lifestyle choice or modern medicine. The two categories are somewhat fuzzy at the borders by these definitions; we hope that advancing medical and biotechnology will move the known and understood aspects of primary aging into the secondary aging category as rapidly as possible.

Habitual use of strange chemicals falls under secondary aging, though I would not be surprised to learn that much of the damage of addiction stems from very poor health practices rather than the chemicals themselves - self-neglect that goes beyond mere lack of exercise and overeating.

Carvalho F. (2009). How bad is accelerated senescence in consumers of drugs of abuse? Adicciones, 21 (2) DOI: ADICCIONES, 2009 - VOL. 21 NUM. 2 - PAGES. 99-104

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Over the years, nanotechnology researcher Robert Freitas has built up an impressive and detailed body of work on how to build real, working nanorobots for medical and human enhancement purposes. In his own words:

My professional goal for the last two decades has been, and continues to be, to help make life-extending medical nanorobotics technologies happen as fast as humanly possible. ... I've been trying to figure out how to build diamondoid nanorobots, starting from current manufacturing technologies.

As noted over at the Foresight Institute, the lastest installment in this large body of work is available for those interested in the path to molecular manufacturing and programmable nanodevices that can repair our cells - or even replace our cells to perform with greater efficiency than evolved biology is capable of achieving.

Robert A. Freitas Jr., author of the Nanomedicine series of books, has just published a major new theory paper on aspects of medical nanorobot control, providing an early glimpse of future discussions of this topic that are planned to appear in Chapter 12 (Nanorobot Control) of Nanomedicine, Vol. IIB: Systems and Operations, the third volume of the series (still in preparation).

...

The chapter is about 5.2 MB in size and a draft preprint version may be downloaded from Freitas' nanomedicine website.

From the paper itself:

Medical nanorobotics is the most powerful form of future nanomedicine technology. Nanorobots may be constructed of diamondoid nanometer-scale parts and mechanical subsystems including onboard sensors, motors, manipulators, power plants, and molecular computers. The presence of onboard nanocomputers would allow in vivo medical nanorobots to perform numerous complex behaviors which must be conditionally executed on at least a semiautonomous basis, guided by receipt of local sensor data and constrained by preprogrammed settings, activity scripts, and event clocking, and further limited by a variety of simultaneously executing real-time control protocols.

If you're new to all this, I strongly suggest you start with a general overview like Chapter 10 of Unbounding the Future: the Nanotechnology Revolution. It may be nearly 20 years old, but the end goals it describes remain the same:

Our bodies are filled with intricate, active molecular structures. When those structures are damaged, health suffers. Modern medicine can affect the workings of the body in many ways, but from a molecular viewpoint it remains crude indeed. Molecular manufacturing can construct a range of medical instruments and devices with far greater abilities. The body is an enormously complex world of molecules. With nanotechnology to help, we can learn to repair it.

Medical nanotechnology (and the medical application of nanorobotics) should be thought of as one future rung on the ladder of advancing biotechnology and computational power. It is a forseeable better way to gain greater control over our cells, and eventually replace those cells with better hardware - a great deal of thought, planning, and development effort is presently going into the precursor technologies that will lead to medical nanorobotics. Look at Zyvex, for example, as one of the present initiatives aimed at building the tools of dry nanotechnology that will lead to molecular manufacturing that will lead to wet nanotechnology and then medical nanorobotics.

Again, this is all about the tools needed to exert greater and more precise control over all the cells in our bodies. We want to be able to manipulate cell state to order, clean out the accumulating junk that damages cells, perform in situ repairs on damage that causes cellular machinery to run awry, and shut down cells before they turn cancerous or senescent, to pick out a few examples. We want to be able to do all these things efficiently and effectively for all of our cells at once. If we can develop technology to perform these tasks well enough, then we can halt aging itself by repairing our biology faster than it falls apart.

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When you spend time following aging and longevity research, thereby becoming immersed in a comparatively small community and conversation, it's easy to lose track of just how unusual your knowledge and viewpoints are in comparison to what passes for the norm. This is true of any group, culture, or endeavor, and is a natural consequence of the economics of learning - most people don't need to know anything about the countless communities outside those they belong to in order to be successful, and you only have a set amount of attention to divide amongst all the things you consider to be important. So "the norm" is really a collective measure of decided ignorance about any given topic. The "the norm" on aging, death by aging, and engineered longevity is what a specialist in some other field - whether astrophysics or bricklaying - is likely know about this topic without expending any significant effort.

Regardless of level of knowledge, everyone will have an opinion, of course. We humans are good at holding opinions - possibly a little too good, but that's evolution for you. Around "the norm" of decided ignorance, holding an opinion has as much to do with learning the prevailing opinion as with actually forming one yourself based on (limited) knowledge. Which again, makes sense from the viewpoint of the economics of time, attention, and knowledge.

This is the hurdle faced by advocates for change in paradigm: it's hard to change opinions when the supporting information for a new viewpoint requires even a moderate amount of effort to obtain and analyze. So it is with aging research and engineered longevity - and most other paradigm changes based on advancing science. You can watch the spread of the ideas of engineered longevity into new discussion communities online; the tech crowd is further ahead than the politics crowd in terms of exposure, for example. But the earliest reactions are still "aging and death are good and needed, and you are most likely crazy for thinking about longevity science." This shows that in terms of advocacy for longer healthy lives, it is still very necessary to keep plugging away at the most basic concepts with the wider audience.

Here is an example of a comparatively well educated online community that is less exposed to thoughts on longevity science - read the comments, and then take a look at this commentary at the IEET:

There were lots and lots and lots of comments that critiqued transhumanism’s rejection of aging and death as natural, necessary, and good. When all the comments are distilled, we get the following arguments:

1) Death and aging is why we value children. Think of the children!
2) Death sweeps away the old, allowing the new
3) We already have too many people! Hello! Malthus!
4) Life extension would result in a nursing home society
5) Can’t do it, aging is too complicated

These are the pillars of "the norm" of opinions on engineering greater human longevity. They are all easily answered, and have been in the post above, here at Fight Aging! and by many other authors, but would that such answers were enough in and of themselves! The realm of public opinion is a long, grinding battle of atttrition that often has little to do with fact, evidence, or anything other than how widespread a particular viewpoint happens to be. Generating much greater public support for longevity science will be a long haul, and no doubt frustrating, but it is absolutely necessary to ensure significant future progress in research and development.

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The Ageing Research blog is back to turning out posts again, the most recent of which focus on cellular senescence in aging. You might look back in the Fight Aging! archives for a general overview of the topic before continuing:

So-called 'senescent' cells are those that have lost the ability to reproduce themselves. They appear to accumulate in quite large numbers in just one tissue (the cartilage in our joints), but even in these small numbers they appear to pose a disproportionate threat to the surrounding, healthy tissues, because of their abnormal metabolic state. Senescent cells secrete abnormally large amounts of some proteins that are harmful to their neighbours, stimulating excessive growth and degrading normal tissue architecture.

In theory our immune system should be scouring the body to destroy senescent cells before they become an issue, but this process slowly fails - along with the other capacities of the immune system - with increasing age. But on to the posts I wanted to point out:

Cellular Senescence in Anti-Ageing Research:

Since senescent cells are potentially detrimental to the tissues in which they reside, anti-ageing research has three main aims for dealing with this problem: (1) Prevention: prevent cells from becoming senescent. (2) Removal: remove senescent cells as they appear. (3) Replacement: replacement of cells which have naturally or artificially been removed.

...

Like all anti-ageing research, [prevention of senescence], senescent cell removal and cell replacement are at their infancy. Only with time, money, a deeper understanding of the ageing process and a motivation to succeed, will we begin to see the inevitable benefits of anti-ageing research.

The removal of senescent cells using therapeutic agents:

At present, no drug-based system exists which can specifically identify senescent cells and remove them. However, there is currently great interest in the development of drugs which specifically target and remove cancer cells. The problem with current cancer treatments (such as drugs used in chemotherapy) is that they are non-specific and as such can cause damage and undesirable changes to non-cancerous cells, causing side-effects. The development of cell-specific drug targeting is greatly needed and such research could be adapted to target senescent cells.

Beyond cancer and damage-causing senescent cells, there are a great many other potential applications for technologies that can kill very specific cell populations. Partially rejuvenating the immune system, for example, by removing the clutter of memory cells uselessly specialized for cytomegalovirus. Or healing autoimmune diseases by wiping out malfunctioning or errantly programmed immune cells. Such technologies even provide the foundation upon which future researchers will build entirely artificial immune systems far more effective and efficient than that provided by our biological heritage.

It's a bright future, and the longer we live, the brighter it will be for us. All the more reason to take care of your health today, so as to maximize your chances of living into the age of repair and rejuvenation.

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My attention was drawn today to a recent open access paper that theorizes on how evolution came to produce the calorie restriction response. Given that calorie restriction notably improves health and longevity, why isn't this beneficial metabolic state switched on all the time?

Stresses like dietary restriction or various toxins increase lifespan in taxa as diverse as yeast, Caenorhabditis elegans, Drosophila and rats, by triggering physiological responses that also tend to delay reproduction. Food odors can reverse the effects of dietary restriction, showing that key mechanisms respond to information, not just resources. Such environmental cues can predict population trends, not just individual prospects for survival and reproduction. When population size is increasing, each offspring produced earlier makes a larger proportional contribution to the gene pool, but the reverse is true when population size is declining.

...

We conclude that the beneficial effects of stress on longevity (hormesis) in diverse taxa are a side-effect of delaying reproduction in response to environmental cues that population size is likely to decrease. The reversal by food odors of the effects of dietary restriction can be explained as a response to information that population size is less likely to decrease, reducing the chance that delaying reproduction will increase fitness.

The bulk of the paper consists of the mathematical model used to argue this point: evolutionary changes that allow animals to delay reproduction at opportune times will be more successful, as will any adaptation that makes metabolism more likely to identify when those opportune times occur. This seems like a solid theory, given the evidence to hand. Population size and its relationship to the availability of food are very fundamental properties, in play for even the earliest and most primitive species, and similar for many diverse species. Thus we should expect to see what we do see in nature: that the calorie restriction response is a very old aspect of animal metabolism, present in almost all species tested, and governed by very similar genetic mechanisms in species ranging from flies to humans.

In the years ahead, researchers will work out how to permanently and safely turn on the calorie restriction response in humans. This seems like a fairly safe prediction absent a specific timeline, given that the research community for this field is well established and companies continue to raise venture funding to develop methods of metabolic manipulation. They will most likely improve on the natural version to some degree once it is fully understood. The flow of newly discovered longevity mutations in lesser species strongly suggests that all species are far from optimized for longevity, and we should expect to find longevity mutations in humans as well.

That said, a likely 20 year timeline to produce tools that do no more than slow aging will be a grand disappointment for those in middle age today. A 2030 in which we cannot repair aging and reverse its effects to any significant degree would be a death sentence - and a well deserved one, given that we had two decades in which to develop more effective medical technologies than metabolic manipulations to mimic the effects of a natural process.

Ratcliff, W., Hawthorne, P., Travisano, M., & Denison, R. (2009). When Stress Predicts a Shrinking Gene Pool, Trading Early Reproduction for Longevity Can Increase Fitness, Even with Lower Fecundity PLoS ONE, 4 (6) DOI: 10.1371/journal.pone.0006055

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